Hydrocodone is a non-natural opioid and one of the most prescribed narcotic drugs. It is primarily used as an orally administered analgesic and antitussive either formulated with acetaminophen or as pure substance. Hydrocodone manufacture and consumption has steadily increased over the past 20 years.
Hydrocodone can be produced by a number of different semi-synthetic pathways, such as from codeine or thebaine. FIG. 1 shows examples of some of these synthetic routes. Codeine is often used as a precursor for hydrocodone synthesis. Codeine is found in the opium poppy plant (papaver somniferum), Codeine can also be obtained by a semi-synthetic pathway from morphine. Codeine can be converted directly to hydrocodone by a single isomerization of the allylic alcohol using ruthenium or rhodium based catalysts. Alternatively, codeine can be converted to dihydrocodeine by transition metal-catalyzed hydrogenation which can then he transformed into hydrocodone by an Oppenauer-type oxidation.
Thebaine can also be as a precursor for hydrocodone synthesis, and, like codeine is also present in the poppy plant, albeit in a lower amount. The generally low amount of thebaine in the opium latex or poppy straw can be significantly enriched by a mutagenized poppy plant, resulting in a remarkable increase of the thebaine production. Thebaine is an attractive precursor to use because it has limited therapeutic use. A direct transformation of thebaine into hydrocodone, however, is not feasible, but a common two-step synthesis can be used. See FIG. 1. Thebaine can be converted to 8,14-dihydrothebaine by a selective double bond reduction. Once formed, the 8,14-dihydrothebaine can be readily hydrolyzed under acidic conditions to hydrocodone.
Unfortunately, the double bond reduction of thebaine to 8,14-dihydrothebaine is difficult. Standard hydrogenation procedures cannot be applied due to severe selectivity problems. For example, hydrogenation procedures using noble metal catalysis suffer from the over-reduction of the diene moiety and hydrogenolysis of the dihydrofuran scaffold. Selective hydrogenation using a strong hydrogenation agent, i.e., diimide (N2H2), also cannot be used because the use of diimide is expensive, uneconomical and prohibitive due to safety issues.
Diimide can predominantly reduce unpolarized carbon-carbon double bonds and can avoid the side-reactions of standard hydrogenation procedures. Yet, diimide is a highly unstable compound which is usually generated in situ. The oxidation of hydrazine (FIG. 2, Method A) and the decomposition of aryl sulfonyl hydrazides (FIG. 2, Method B) are two known methods to generate diimide in situ for subsequent olefin reductions. Sulfonyl hydrazides, such as p-toluenesulfonyl hydrazide (TSH), can be used in combination with stoichiometric amounts of a weak base to generate diimide in situ. Using organic sulfonyl hydrazides is complex and expensive. The reaction is also slow requiring the use of metal and organocatalysts to enhance the reaction rate of the initial oxidation step. A more economical (atom) and less expensive (monetary) synthetic route is oxidizing hydrazine with oxygen gas (O2) to form diimide in situ. This synthetic route has been discouraged in the literature, however, as involving serious safety concerns (“This process involved the use of gaseous oxygen, which is hazardous on an industrial scale since mixtures of hydrazine vapour and oxygen are potentially explosive, and employed a molar ratio of hydrazine to thebaine of 53:1 which is commercially unattractive” U.S. Pat. No. 3,812,132 (1974), the disclosure of which is incorporated herein in its entirety).
These concerns have been addressed by the present disclosure which relates to selective reduction of morphinan alkaloids, including thebaine to 8,14-dihydrothebaine, using diimide generated in situ in a continuous flow system.